Value of Dedicated Head and Neck 18F-FDG PET/CT Protocol in Detecting Recurrent and Metastatic Lesions in Post-surgical Differentiated Thyroid Carcinoma Patients with High Serum Thyroglobulin Level and Negative 131I Whole-body Scan

Objective(s): In clinical practice, approximately 10-25% of post-surgical differentiated thyroid carcinoma (DTC) patients with high serum thyroglobulin (Tg) and negative 131I whole-body scan (WBS) have poor prognosis due to recurrent or metastatic lesions after radioactive iodine treatment. The purpose of this study was to evaluate the value of 18F-FDG PET/CT scan in DTC patients with high serum Tg level and negative 131I WBS. Methods: 69 post-surgical DTC patients with high serum Tg level and negative post ablation 131I WBS were enrolled in this study. All DTC patients underwent head and neck ultrasound, CT scan and whole-body 18F-FDG PET/CT, based on the dedicated head and neck protocol. Results: Overall, 92 lesions were detected in 43 (62.3%) out of 69 patients with positive 18F-FDG PET/CT scan, compared to only 39 lesions detected on CT scan in 26 (37.7%) out of 69 patients. The sensitivity, accuracy and negative predictive value of 18F-FDG PET/CT were 88%, 87% % and 76%, respectively, which were significantly higher than those of CT scan (67.2%, 54.3% and 48.8%, respectively) (P<0.01). Specificity and positive predictive value of 18F-FDG PET/CT (90.5% and 95.2%, respectively) were similar to those of CT scan (95.2% and 96.2%, respectively) (P>0.05). The maximum standardized uptake value (SUVmax) threshold was 4.5 with a good diagnostic value (sensitivity of 92.3% and specificity of 100%). The dedicated head and neck 18F-FDG PET/CT protocol altered the treatment plan in 33 (47.8%) out of 69 DTC patients with high serum Tg level and negative 131I WBS. Conclusion: Dedicated head and neck 18F-FDG PET/CT protocol showed a higher diagnostic value, compared to CT scan and played an important role in detecting recurrent or metastatic lesions in post-surgical DTC patients with high serum Tg level and negative 131I WBS.


Introduction
In Vietnam, thyroid cancer is the sixth most common malignant disease, following lung, breast, prostate, cervical and hepatocellular carcinomas in both men and women (1). Differentiated thyroid carcinoma (DTC), which accounts for 90% of all thyroid cancers, often has a good prognosis due to radioiodine avidity. However, the rate of recurrence and metastasis remains high in high-risk DTC patients. Overall, 10-25% of patients with DTC may experience tumor recurrence and/ or metastasis in the course of their life (2).
Traditionally, after total thyroidectomy and remnant ablation with radioactive iodine (RAI), DTC patients are followed-up to detect recurrence and metastasis by serum thyroglobulin (Tg) and diagnostic iodine-131 ( 131 I) whole-body scan (WBS). Determination of abnormalities in serum Tg level and 131 I WBS plays a significant role in clinical decision-making by nuclear medicine physicians.
According to our statistical data, 15-20% of DTC patients have high serum Tg level, despite negative 131 I WBS (positive Tg and negative 131 I WBS) after 131 I therapeutic courses (3). Lack of response to RAI therapy is predicted in these patients, who have a poorer prognosis, compared to others. In case 131 I WBS cannot detect recurrent or metastatic lesions in DTC patients with high serum Tg level, other diagnostic imaging modalities such as computed tomography (CT), neck ultrasound, magnetic resonance imaging (MRI) and fluorine-18 fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/ CT are recommended as complementary methods (4). Findings obtained by conventional imaging modalities (e.g., ultrasound, CT and MRI) are often equivocal in many cases with post-surgical structural changes.
Nowadays, 18 F-FDG PET/CT by fusing anatomic and molecular imaging is considered as an effective modality in many malignant diseases (5). Several studies have confirmed the value of whole-body 18 F-FDG PET/CT scan in DTC patients with positive Tg and negative 131 I WBS, despite its limitations in post-surgical examination of head and neck regions (6). However, to the best of our knowledge, a limited number of studies have evaluated the value of 18 F-FDG PET/CT in DTC patients in Vietnam.
In our center, dedicated head and neck 18 F-FDG PET/CT protocol has been proposed for routine application in order to increase the diagnostic accuracy. Therefore, the main purpose of this study was to evaluate the utility of dedicated head and

Methods
In the present study, 69 DTC patients with negative post-therapeutic 131 I WBS and high Tg level (> 2 ng/ml) after thyroid hormone withdrawal associated with normal anti-Tg level, were selected at the Department of Nuclear Medicine, Tran Hung Dao Hospital, Hanoi, Vietnam during April 2010-August 2013. Informed consent forms were signed by all participants, as required by the medical ethics committee of the hospital.
Patients underwent 18 F-FDG PET/CT scan, using the dedicated head and neck protocol. The diagnostic values of CT and 18 F-FDG PET/CT were analyzed, based on relevant pathologic and histologic results and follow up(every six-months).
PET/CT examination was performed, using GE Discovery Lightspeed 16-slice CT scan (STE), according to the European Association of Nuclear Medicine (EANM) guidelines, version 1.0 (7).
For patient preparation, the serum glucose level was checked to exclude hyperglycemia. Afterwards, the patients were allowed to rest in the waiting room before intravenous injection of 2.5 MBq/kg body weight (±10%) of 18 F-FDG. PET and low-dose CT scans from the skull base to the mid-thigh were performed 60 min after 18 F-FDG injection as the standard procedure.
Subsequent to the whole body PET/CT imaging, the dedicated head and neck protocol was applied. If the head and neck diagnostic CT scan with contrast enhancement was not available within four weeks prior to 18 F-FDG PET/CT scan, the dedicated head and neck 18 F-FDG PET and CT scan,  Figure 1. Images of a 65-year-old male patient with papillary thyroid cancer undergoing total thyroidectomy and 131 I therapy with a total dose of 550 mCi. 131 I WBS after the third treatment session showed no abnormal uptake and the patient's stimulated thyroglobulin was > 1000 ng/ml. (B) axial PET and (C) axial PET/CT images revealed increased focal 18 F-FDG uptake in thyroid bed and pretracheal lymph node, which is not clearly seen in low-dose CT (A). Surgical resection of these lesions confirmed recurrence/metastasis of papillary thyroid carcinoma Figure 2. Dedicated head and neck 18 F-FDG PET/CT with contrast enhancement in a 60-year-old male patient with a prior history of thyroid papillary carcinoma and total thyroidectomy. The patient presented with a serum thyroglobulin level of 1000 ng/ml and negative post-therapeutic 131 I WBS. The axial PET image illustrated focal 18 F-FDG uptake (SUV max :7.6), correlated with the sub-centimeter lymph node on the left IIA level. 18 F-FDG PET/CT with contrast enhancement precisely localized the lesion which may be confused as normal on CT imaging alone. After resection, the histopathological results indicated metastatic lymph node of thyroid carcinoma using an intravenous contrast, were performed.
The dedicated head and neck protocol was acquired from the cranial top to the thoracic inlet in an arm-down position. Briefly, PET images were obtained in a three-dimensional mode, two bed positions (for 6 min per bed position), 30 cm transaxial field of view (FOV), iterative reconstruction, 20 subsets/2 iterations and a matrix size of 256×256.
Attenuation correction was based on contrastenhanced CT scan (if present). The parameters of head and neck CT scan were as follows: 120 kVp, 100 mA, helical thickness of 3.75 mm, matrix size of 512×512, FOV of 30 cm and 0.5 s/ rotation. Overall, 100 ml of the contrast material was used (if necessary) with a scan delay of 30 s and an injection rate of 3 ml/s (8). Tumornode-metastasis (TNM) staging was used for risk stratification, according to the classification by the American Joint Committee on Cancer (AJCC) (9).
In general, 18 F-FDG PET/CT was read independently by one of two nuclear medicine physicians with thorough knowledge about the patient's clinical history; then, the other physician reviewed all lesion-related findings and impressions. Disagreements were resolved by consensus. A positive lesion on F-18 FDG PET/ CT imaging was defined as a focal FDG uptake with relatively higher activity than that of the surrounding normal tissue or when the SUV max of the lesion was revealed to be more than 2.5.
All detected lymph nodes were measured and a threshold of 10 mm was considered for pathologic lymph nodes (10). The diagnosis of recurrent and metastatic lesions was confirmed by histopathologic results or follow-up for at least 12 months. The diagnosis was confirmed by elevation in serum Tg level (≥10 ng/ml after T 4 withdrawal) or other imaging modalities such as neck ultrasonography and CT scan.
The statistical analysis was performed, using SPSS version 16.0 (SPSS Inc, Chicago, IL). The sensitivity, specificity, positive and negative predictive values and accuracy of 18 F-FDG PET/ CT and CT scan were analyzed, and the confidence intervals (95%) were determined.

Results
In total, 69 DTC patients including 13 males (18.8%) and 56 females (81.2%), with negative 131 I WBS and high serum Tg level, were admitted to our center for dedicated head and neck 18 F-FDG PET/CT examination ( Table 1).
The characteristics of lesions on CT and 18 F-FDG PET/CT scans are presented in Table 2. In total, 92 lesions were detected in 43 patients (62.3%) on 18 F-FDG PET/CT, compared to only 39 lesions detected in 26 patients (37.7%) on CT scans. 18 F-FDG PET/CT could detect more malignant lesions in thyroid beds, cervical lymph nodes and distant metastases, compared to CT scan alone (Figures 1, 2 & 3).
The area under the receiver operating characteristic (ROC) curve of 18 F-FDG PET/CT (0.887) was significantly larger than that of CT scan (0.748), as presented in Figure 4. The overall results indicated that 18 F-FDG PET/CT examination is superior to CT scan in the diagnosis of recurrent and/or metastatic DTC.
Based on positive 18 F-FDG PET/CT findings, the treatment strategy directly changed in 33 (47.8%) out of 69 DTC patients. Particularly, 31 (86%) out of 33 patients required further surgeries and 2 (4%) out of 33 patients were refferred for external beam radiation therapy. The empiric 131 I therapy was performed on 27 (39%) out of 69 cases. Also, in 9 (13.2%) out of 69 patients with negative FDG-PET/CT imaging, further treatment was not justified, and this group was pursued to follow the watchful waiting strategy (Table 3).

Discussion
The present study demonstrated that dedicated head and neck 18 F-FDG PET/CT scan is  (12). However, these values seem to be lower than the presented data in our study, which might be due to the smaller number of patients and differences in the selected patient populations in studies by Bannas et al. and Shammas and colleagues.
As confirmed by other studies, the sensitivity of 18 F-FDG PET in DTC patients with negative I-131 WBS and high serum Tg level is also dependent on 18 F-FDG uptake (13) (14). Generally, the anatomical landmarks and post-operative structures of the head and neck regions may be confusing for radiologists and nuclear medicine physicians in interpreting 18 F-FDG PET/CT images. Several earlier studies using dedicated head and neck 18 F-FDG PET/CT protocol showed that the sensitivity, specificity and accuracy of this modality may be improved compared to conventional method in order to assure nuclear medicine physicians about the analysis of structural complexity of head and neck regions (15,16).
In our study, the dedicated head and neck 18 F-FDG PET/CT protocol and contrast enhancement could provide better results, compared to the routine whole-body 18 F-FDG PET/CT scan in detecting and localizing regional recurrences and/or metastatic lesions in postsurgical DTC patients. In head and neck PET/CT protocol, some technical CT and PET parameters have been modified to cover the neck region and all regional lymph nodes. Furthermore, Terence el al. suggested that imaging quality improvements in the dedicated protocol may result in artifact elimination which could well define the adjacent anatomy (8).
Schlutter et al. performed 18 F-FDG PET scan on 64 DTC patients with positive Tg and negative 131 I WBS and illustrated that 18 F-FDG PET was positive in 44 and negative in 20 patients (17). Overall, 34 true positive lesions were detected, which required surgery and/or external beam radiation therapy after 18 F-FDG PET/CT scan in 19 out of 34 patients. Positive and negative predictive values of 18 F-FDG PET/CT for detecting recurrence/ metastasis were 83% and 25%, respectively. Also, Na et al. studied 54 DTC patients with negative 131 I WBS, using off-T 4 , and 18 F-FDG PET. In this study, the sensitivity and specificity of 18 F-FDG PET in detecting recurrence/metastasis were 93.9% and 95.2%, respectively (18).
In the present study, 43 (62.3%) out of 69 DTC patients had positive 18 F-FDG PET/CT results, meanwhile only 26 (37.7%) cases had positive CT results. The number of lesions detected on 18 F-FDG PET/CT was more than twice the number detected on CT scan (92 lesions on PET/CT, compared to 39 lesions on CT scan). Therefore, 18 F-FDG PET/CT was superior to CT scan in detecting recurrence  and metastasis in DTC patients with high Tg level and negative 131 I WBS. 18 F-FDG PET/CT examination has the advantage of detecting both glucose metabolism in PET and abnormal anatomic changes in CT scan (19). In general, the criterion for suspecting metastatic cervical lymph nodes on CT scan was enlarged lymph nodes with the largest dimension greater than 10 mm (10) (20). However, in our study, 16 (37.2%) out of 43 patients had positive 18 F-FDG PET lymph nodes less than 10 mm in diameter, whereas recurrence and metastasis were confirmed by post-operative histopathology in 10 patients. Consequently, there would be an underestimation if this criterion was taken into account for the interpretation of CT images.
The diagnostic accuracy of 18 F-FDG PET/CT for recurrent and metastatic thyroid carcinoma is also related to increasing serum Tg level (21). The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of 18 F-FDG PET/CT were 69.4%, 66.7%, 69.1%, 95.6% and 17.4%, respectively. Therefore, the diagnostic accuracy of 18 F-FDG PET/CT scan in DTC patients with positive Tg and negative 131 I WBS may depend on serum Tg level at the time of imaging.
Overall, 18 F-FDG PET/CT scan is useful for the detection and localization of malignant recurrences in patients with negative diagnostic radioiodine scan, despite elevated Tg level greater than 20 ng/ ml or high anti-Tg level. However, 18 F-FDG PET/ CT provides little additional information when Tg level is lower than 5 ng/ml (18).
Among 31 patients with positive 18 F-FDG PET/ CT undergoing surgical resections, recurrence and metastasis were histopathologically confirmed in 30 patients, and only one patient had negative post-operative histopathological results. However, three patients with negative 18 F-FDG PET/CT results had metastatic cervical lymph nodes during 6-12-month follow-up after 18 F-FDG PET/CT scans. Therefore, 18 F-FDG PET/CT results may be false positive due to FDG uptake in inflammatory lesions or false negative in case of microscopic metastatic diseases below the resolution of PET.
Principally, it is important that 18 F-FDG PET/ CT results be accompanied by patient's clinical characteristics, other diagnostic tools as well as close follow-up in DTC patients using serum Tg and neck ultrasound (22). Undoubtedly, 18 F-FDG PET/ CT is more powerful than CT alone in detecting recurrent and metastatic lesions in DTC patients with high Tg level and negative 131 I WBS.
On the other hand, 18 F-FDG PET/CT is costly and unavailable in many nuclear medicine departments in developing countries such as Vietnam. As a result, the combination of conventional imaging modalities such as neck ultrasound and Tc-99m sestamibi SPECT/CT can be a reasonable approach for DTC patients with high Tg level and negative 131 I WBS in hospitals not equipped with a PET/CT unit.
In the present study, after performing 18 F-FDG PET/CT scan, 31 patients underwent surgical resections and two cases received external beam radiation therapy. Therefore, the treatment strategy changed in 33 out of 69 patients (47.8%), based on the results of 18 F-FDG PET/CT imaging. In a study by Nahas et al., the treatment plan changed in 40% of patients, based on the FDG-PET/CT data (23).
The ability of FDG-PET/CT in detection of recurrent and metastatic lesions may affect the clinical results. As more positive lesions are detected, more patients are considered to require changes in the treatment strategies. On the other hand, in a group of patients, who cannot be treated by surgery or radiation therapy, other strategies should be considered. Empiric 131 I therapy may be a suitable modality for these patients. Kuang et al. revealed that Tg level decreased in 63% of DTC patients after empiric 131 I therapy (24). As the authors suggested, empiric therapy may be effective when Tg level is considered as an index of tumor burden.

Conclusion
As the results indicated, the dedicated head and neck 18 F-FDG PET/CT protocol was useful for the detection and localization of recurrent and/or metastatic lesions in post-surgical DTC patients with a high serum Tg level and negative 131 I WBS. We recommend that treatment decision-making for these patients be based on 18 F-FDG PET/CT results.